Mutant WDR45 Leads to Altered Ferritinophagy and Ferroptosis in ß-Propeller Protein-Associated Neurodegeneration.
Int J Mol Sci
; 23(17)2022 Aug 23.
Article
in En
| MEDLINE
| ID: mdl-36076926
ABSTRACT
Beta-propeller protein-associated neurodegeneration (BPAN) is a subtype of neurodegeneration with brain iron accumulation (NBIA) caused by loss-of-function variants in WDR45. The underlying mechanism of iron accumulation in WDR45 deficiency remains elusive. We established a primary skin fibroblast culture of a new BPAN patient with a missense variant p.(Asn61Lys) in WDR45 (NM_007075.3 c.183C>A). The female patient has generalized dystonia, anarthria, parkinsonism, spasticity, stereotypies, and a distinctive cranial MRI with generalized brain atrophy, predominantly of the cerebellum. For the functional characterization of this variant and to provide a molecular link of WDR45 and iron accumulation, we looked for disease- and variant-related changes in the patient's fibroblasts by qPCR, immunoblotting and immunofluorescence comparing to three controls and a previously reported WDR45 patient. We demonstrated molecular changes in mutant cells comprising an impaired mitochondrial network, decreased levels of lysosomal proteins and enzymes, and altered autophagy, confirming the pathogenicity of the variant. Compared to increased levels of the ferritinophagy marker Nuclear Coactivator 4 (NCOA4) in control cells upon iron treatment, patients' cells revealed unchanged NCOA4 protein levels, indicating disturbed ferritinophagy. Additionally, we observed abnormal protein levels of markers of the iron-dependent cell death ferroptosis in patients' cells. Altogether, our data suggests that WDR45 deficiency affects ferritinophagy and ferroptosis, consequentially disturbing iron recycling.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Carrier Proteins
/
Neurodegenerative Diseases
/
Ferroptosis
Type of study:
Risk_factors_studies
Limits:
Female
/
Humans
Language:
En
Journal:
Int J Mol Sci
Year:
2022
Document type:
Article
Affiliation country: